This application responds to RFA-AG-20-013 entitled Worldwide aging-associated Approaches to Alzheimer's increase in life expectancy has produced a dramatic rise in the prevalence, and thus impact of diseases, including Alzheimer's disease (AD). There is no effective treatment to halt or slow ?Geroscience Disease?. AD, and progress made in the development of new therapies is disappointing since many new compounds, despite initial promise at the preclinical level, failed in clinical trials (Cummings et al., 2018). The biggest risk factor for AD is aging. Therefore, novel approaches detecting mechanistic link between aging and AD at the cellular level, that leads to prodromal neuronal dysfunctions associated with later cognitive impairment and dementia, core features of AD, are crucial for identifying therapeutic interventions that have potential to modify course of disease. Our precedes promoting relevant the pharmacological manifestation are Specific Specific recent published and preliminary results showed that dyssynchronous activity of neuronal ensembles onset of symptoms in rat and mouse models of AD. We also identified hypothalamic hunger- neurons expressing Agouti-related peptide (AgRP) as crucial determinant of systemic metabolism to calorie restriction, aging and higher brain functions. These observations collectively gave impetus to central hypothesis of this proposal, which is that suppression of aging by nutrient (calorie restriction) or (FGF21) interventions will delay t he onse of electrophysiological, behavioral and pathological of impairments in animal models of AD. We also hypothesize that hypothalamic AgRP neurons central to the beneficial effects of these interventions. To test these hypotheses, we propose the following Aims: Aim 1 t will test the hypothesis that calorie restriction and FGF21 treatment suppress subclinical and clinical symptom development and brain pathologies in a transgenic rat model (TgF344-AD) of AD expressing mutant human amyloid precursor protein (APPswe) and presenilin 1 (PS1?E9) genes. Specific Aim 2 will of pathologies interrogate the hypothesis that hypothalamic AgRP neurons are critical for mediating effects calorie restriction and FGF21 in modulation of subclinical and clinical symptoms development and brain in transgenic mouse models (5xFAD and Tg2576) of AD. To execute these Specific Aims we will utilize rat and mouse models of AD with nutrient and pharmacological interventions, the combination of in vivo electrophysiology, behavioral analyses, biochemistry and pathological evaluation of control and experimental animals. Our studies will directly and forcefully analyze the relationship between aging-related systemic and cellular processes using electrophysiological (EEG), behavioral, histological and biochemical methods to track symptoms development of AD in known animal models. The outcome of these studies will immediately suggest possible interventions to alter AD development in primates, including humans.